Synthesis And Structure-function Relationship Study Of Selective 11?-HSD1 Inhibitors

Diabetes mellitus(DM)is a metabolic disease characterized by hyperglycemia caused by defective insulin secretion and(or)dysfunction of insulin,is one of the chronic killers seriously endangering people's health.11?-HSD1 can catalyze the conversion of inactive corticosterone into active cortisol,thereby increasing the level of glucocorticoid in local tissues.Studies have found that 11?-HSDl inhibitors can reduce glucocorticoid activity,improve insulin sensitivity and pancreas islet B cell function,reduce liver sugar output,and thereby control blood glucose.Hupehenol A-E is five natural selective 11?-HSD1 inhibitors that our group isolated from Viburnum hupehense.Among them,Hupehenol B can inhibit human 11?-HSD1 to the nmol level(IC50 = 15.3 nM),which is a potential diabetes treatment drug.Inspired by natural 11?-HSD 1 inhibitors hupehenols A-E,a ring-focused strategy was applied for thesynthesis of 35 structurally diverse dammarane-type derivatives.These derivatives were effectively prepared from protopanaxadiol based on the modification of rings A and D.Among these compounds,ten were identified as selective 11?3-HSD1 inhibitors,of which 5 compounds showed significant inhibitory effects on human 11?-HSD1(IC50 range:101-1047 nM,SI range:8-9),and 4 compounds showed significant inhibitory effects on mouse 11?-HSD1(IC50 range:101-1047 nM,SI range:16-169).Otherwise,we found 23a couldselectively inhibit both human and mouse 11?-HSDI with IC50 value of 994 and 213 nM(SI>10 and>47),respectively.Additionally,the molecular modelling results of 23a docking into the human andmouse 11?-HSD1 were in good agreement with the results from the enzyme inhibitory experiment.Moreover,valuable structural-activity relationship(SAR)information of dammarane-type 11?-HSD1 inhibitor was summarized.Based on the previous experimental results,we speculated that the 15-site carbonyl group might be an important active site.In order to obtain more active 11?-HSD1 inhibitors,we decided to directly modify its structure with Hupehenol B as the substrate.In the process of semi-synthesis of Hupehenol B,this route was also optimized in order to obtain 15-position carbonyl compounds as soon as possible.Finally,eight derivatives with different structures were synthesized through the modification of C3,C12 and D-ring,among which one compound identified as mouse 11?-HSD1 inhibitors(IC50 = 0.36[,M).Moreover,valuable structural-activity relationship(SAR)information of Hupehenols derivatives was summarized.